WO2003030871A1 - Traitement de poudre avec des fluides gazeux sous pression - Google Patents

Traitement de poudre avec des fluides gazeux sous pression Download PDF

Info

Publication number
WO2003030871A1
WO2003030871A1 PCT/US2002/032303 US0232303W WO03030871A1 WO 2003030871 A1 WO2003030871 A1 WO 2003030871A1 US 0232303 W US0232303 W US 0232303W WO 03030871 A1 WO03030871 A1 WO 03030871A1
Authority
WO
WIPO (PCT)
Prior art keywords
solid
semi
particles
carrier material
solution
Prior art date
Application number
PCT/US2002/032303
Other languages
English (en)
Inventor
Said Saim
Stephen Horhota
David Joseph Bochniak
Kenneth J. Koenig
Original Assignee
Boehringer Ingelheim Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to DE60211004T priority Critical patent/DE60211004T2/de
Priority to IL16093102A priority patent/IL160931A0/xx
Priority to JP2003533904A priority patent/JP2005511521A/ja
Priority to MXPA04003321A priority patent/MXPA04003321A/es
Priority to CA2462338A priority patent/CA2462338C/fr
Priority to BR0213155-2A priority patent/BR0213155A/pt
Priority to EP02800989A priority patent/EP1435916B1/fr
Priority to NZ532759A priority patent/NZ532759A/en
Application filed by Boehringer Ingelheim Pharmaceuticals, Inc. filed Critical Boehringer Ingelheim Pharmaceuticals, Inc.
Priority to EA200400483A priority patent/EA006064B1/ru
Priority to AU2002334935A priority patent/AU2002334935B2/en
Priority to YU29104A priority patent/RS29104A/sr
Publication of WO2003030871A1 publication Critical patent/WO2003030871A1/fr
Priority to HR20040334A priority patent/HRP20040334A2/hr
Priority to HK05102734A priority patent/HK1069994A1/xx

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • This application generally relates to a method that employs a pressurized gaseous fluid for processing out of solution particles of a solid or semi-solid material for simultaneously retaining and dispersing these processed particles in a carrier material.
  • This technique can be advantageously used in pharmaceutical and chemical processing to produce a blend of the solid or semi-solid material particles and carrier material, a granulation of the solid or semi-solid material particles with carrier material, carrier material partially or fully coated with the solid or semi-solid, material particles, or mixtures thereof.
  • Solid dosage forms for pharmaceuticals such as tablets and capsules require the use of fine powders of drug substance material in order to achieve uniform distribution of the pharmacologic agent in these powder-based formulations. Additionally, drug substances with very low solubility and dissolution rates often need to be reduced in size to levels on the order of 10 ⁇ m or less in order to achieve satisfactory bioavailability. In some cases, particles ⁇ 1 ⁇ m are necessary for drugs with exceptionally poor aqueous solubility.
  • a supercritical fluid is a substance above its critical temperature and critical pressure (31 °C, 1,070 psi for CO 2 ).
  • a SCF such as CO 2 is essentially a compressed, high diffusivity and high density fluid at mild temperature. It is relatively innocuous, inexpensive, and unreactive. SFE is often used to selectively extract a variety of compounds. After extraction, the SCF mixture is expanded into a collection vessel held at a lower pressure. Because of the low solvent power of the low-pressure gas, the compound precipitates and is collected in a vessel. The effluent low pressure gas is vented out or recycled into the process.
  • a wealth of information on the properties of SCFs is available in the technical literature (McHugh, M. and Krukonis, V., Supercritical Fluid Extraction, Principles and Practice, 2 nd Ed., Butterworth-Heinemann, Boston. 1993).
  • SFE has been used to produce phannaceutical powders (Larson, K.A. et al., Biotechnology Progress 2 (2), June 1986, pp. 73-82), it is normally used for selective extraction of SCF-soluble material from raw substrates where the particle size of the extracted material following depressurization is generally not a concern of the process.
  • a particularity of SFE is that it can be used to extract desirable materials as well as impurities in any physical form: liquid, solid or semi-solid.
  • a solute substance is placed in a high-pressure vessel.
  • a SCF is then pumped through the vessel to dissolve the substance and form a solution of the substance in the SCF.
  • the fluid mixture is then expanded through a nozzle into a vessel held at a substantially lower, sub-critical pressure where the fluid is now a low density gas. Because of the low solvent power of the low-pressure gas, the substance precipitates and is collected in the vessel.
  • the large pressure differential across the nozzle causes the expansion to take place at ultrasonic velocity and supersaturation to increase rapidly. The rapid expansion translates into a rapid change in the density and solvent power of the fluid and therefore into rapid crystallization rates which result in the formation of small microparticles and nanoparticles of the substance.
  • Effluent gas is passed through a micro-filter and then vented or recycled.
  • An alternative way to rapidly reduce the solvent power of the SCF without any substantial change in pressure consists of contacting the SCF solution with an inert gas such as nitrogen or helium where the solute substance is substantially insoluble.
  • the inert gas may be kept at a pressure similar to that of the SCF solution. The inert gas rapidly mixes with the SCF to cause its solvent power to decrease and the solute to precipitate.
  • the SCF may be used as an antisolvent.
  • the GAS process (U.S. patent 5,360,478; U.S. patent 5,389,263) was first reported at an international meeting of the American Institute of Chemical Engineers (Paper 48c at the AIChE Meeting, Nov. 29, 1988) and later by Gallagher, P.M. et al. (Chap 22, Supercritical Fluid Science and Technology, ACS Symposium Series, 406, Washington, DC, K.P. Johnston, J.M.L. Penninger, ed., ACS Publishing, 1989).
  • a SCF is used as an antisolvent to process a SCF-insoluble solute from a pre- mixed batch of an organic solution of the solute by adding a SCF into the solution. Addition of the SCF causes its concentration in the solution to increase and the solution to expand. Solute precipitation takes place when the solution becomes supersaturated.
  • the batch GAS process is limited in its ability to process large quantities of material.
  • the organic solution of the solute is added continuously to continuously flowing SCF antisolvent.
  • the organic solvent rapidly mixes and dissolves in the SCF to form a homogeneous high-pressure fluid mixture. Because the solute is substantially insoluble in the SCF and the SCF and the organic solvent are miscible, this results in its precipitation in the high pressure vessel.
  • the SCF-organic solvent mixture is passed through a micro-filter and then expanded into a low pressure vessel where the SCF separates from the organic solvent.
  • the SAS process is suitable for processing thermally labile substances. Unlike other processes such as conventional spray drying where the rate of solvent removal from droplet surfaces is relatively slow and depends to a large extent on processing temperature, in this process such rate depends primarily on the density and flow rate of the SCFs. Both parameters can easily be controlled over a wide range at a relatively low temperature to control the rate of solvent removal over an equally wide range.
  • Coenen et al. (US Patent 4,828,702) report a countercurrent process whereby a liquid solution of a solid solute is sprayed into a SCF antisolvent such as CO 2 to recover the solid material as a powder.
  • Fisher and Muller report a process whereby a liquid solution of active substance is sprayed as a fine mist into a SCF solution of a carrier material to produce sterile microparticles of active substance embedded within carrier material.
  • Yeo et al. Biotechnology and Bioengineering, 1993, Vol. 41, p. 341) and Debenedetti (U.S. Patent 6,063,910) also describe a process whereby the solution is sprayed as a fine mist across a nozzle into a high pressure vessel containing a SCF in order to produce fine powders of the solute.
  • Schmidt U.S.
  • patent 5,707,634 reports a process whereby a non-sterile solute is recovered from a solution injected into a high-pressure vessel containing a SCF antisolvent.
  • Subramaniam et al. U.S. Patent 5,833,891 describe a process whereby an ultrasonic nozzle is used to enhance the atomization of the liquid solution spray which aids in the production of finely divided microparticles and nanoparticles of active material.
  • SAS Anasol Solvent Extraction Systems
  • SEDS Solution- Enhanced Dispersion by SCFs
  • SEDS U.S. Patents 5,851,453 and 6,063,138
  • SEDS involves using a coaxial, non-ultrasonic nozzle.
  • High mass transfer rates are achieved with a high ratio of supercritical fluid to solvent and the high velocities of the SCF facilitate the atomization of the solution.
  • Subramaniam et al. (U.S. Patent 5,833,891) describe a process whereby particles are crystallized from a liquid solution and directed at a bed of fluidized core particles to form a coating. In this process, the SCF is used to both fluidize the core particles and to effect the crystallization of the coating substance out of the solution. The process can be used in a manner similar to the classic Wurster coating process.
  • Benoit et al. U.S. Patent 6,087,003 describe a batch process whereby an active substance is stireed in a high pressure vessel containing a SCF and a coating material dissolved therein.
  • the temperature of the SCF is then gradually lowered to a point where it separates into a gas phase and a liquid phase where the core particles are in suspension and the coating material is in solution. Continuous removal of the gas phase causes the concentration of the coating material in the liquid phase to increase and its solubility to decrease. This results eventually in the precipitation of the coating material on the active substrate. Because of the possibly limited solubility of coating material in a batch of SCF, the process may be repeated using pre-loaded coating material attached to the shaft of the stirring device. Smith (U.S. Patent 4,582,731) discusses aprocess whereby particles fonned by RESS are directed at and adhered to solid surfaces such as glass, fused silica and platinum to form a thin film coating.
  • Processes described above are designed to produce either coated substrates or microparticles or microcapsules of a particular substance.
  • a premise for the present invention is that in the pharmaceutical industry, fine drug powders are rarely used as final solid state formulations because collection, handling, flow, and/or compression of powders of microparticles and nanoparticles can be very challenging. A micronized powder of a particular drug substance is therefore rarely used without further processing. If one desires to make a solid state pharmaceutical formulation of a drug substance, it is generally necessary to mix the drug microparticles or nanoparticles with particles of carrier substance(s). Such carriers, such as lactose, exhibit good handling, flow, and compression properties.
  • Specialized fluidization equipment normally does not allow for stirring but provides for a carefully controlled pressure differential within the vessel to effect fluidization of particles, uniform distribution of the fluidizing gas, control of bed expansion, and collection of fines.
  • the superficial velocity of suspending fluid is critical; too high a velocity will cause the core particles to become entrained onto the filter; too low a velocity may result in incomplete expansion/fluidization of the bed.
  • precipitation and drying happens very quickly in SCF processing, the droplets may be dried prior to contacting the core particles and the very small crystals that are produced can easily be entrained in the suspending fluid. Therefore, precipitation with adhesion to the core particles may not occur consistently, and some precipitated particles may become separated from the bed of core particles.
  • a drawback of RESS, GAS and SAS processes is the difficulty of trapping, collecting and handling fine powders of microparticles and nanoparticles. Filters used in these processes are generally not capable of effectively retaining the produced microparticles and nanoparticles. If filter pores are small enough to retain such particles, the filter can become rapidly plugged up by the particles. This can severely restrict flow through the crystallization vessel, and frequent interruptions to clean or replace filters may become necessary.
  • resistance to flow causes pressure in the vessel to rise appreciably and the pressure drop across the nozzle to decrease. At some point, the pressure drop vanishes completely and the process would need to be halted.
  • SAS resistance to flow could also cause pressure in the vessel to continuously rise throughout the process.
  • microparticles Even if microparticles can be retained by such devices as cyclones, they present handling difficulties. Flow characteristics of powders containing microparticles and/or nanoparticles are generally poor. Such powders may therefore be difficult to discharge and use in downstream processes. Further processing by such processes as mixing with carrier material and granulation may therefore still be necessary before incorporation into a formulation. Powders with poor flow characteristics are difficult to incorporate into carrier material and normally require special blending procedures or techniques to obtain the required blend unifonnity. Fine powders are also difficult to handle because of their dustiness. Special operator protection is required and very specific procedures are required for potent drugs or toxins.
  • the present invention is in general directed to a method for solute particle precipitation, retention and dispersion in a carrier material by taking advantage of the unique properties of pressurized gaseous (e.g. supercritical) fluids to precipitate solute particles from solution and by effectively retaining and dispersing the precipitated particles in a carrier material having good flow and handling properties.
  • a solute may be precipitated from either a liquid solvent or a pressurized gaseous fluid solution. As described herein, this process has broad applicability in the pharmaceutical industry.
  • the method of the present invention involves: (a)(1) dissolving a solid or semi-solid material in a pressurized gaseous fluid, thereby forming a solution comprising a gaseous fluid solvent and a dissolved solute of solid or semi-solid material or
  • step (b)(2) precipitating particles of the solid or semi-solid material out of the liquid solution produced in step (a)(2) by introducing the solution into either: (1) a region containing a pressurized gaseous fluid in which said liquid solvent is substantially soluble but said solid or semi-solid material is substantially insoluble, or (2) a region into which said pressurized gaseous fluid is subsequently introduced to cause the solubilization of the liquid solvent into the pressurized gaseous fluid and the precipitation of the particles of the solid or semi-solid material;
  • step (c) directing the introduced solution and resulting precipitated particles produced in step (b)(1) or (b)(2) onto or into a mixed bed of carrier material;
  • the present method is applicable to the precipitation (or crystallization) of a wide variety of solid and semi-solid materials, e.g., physiologically active materials, encapsulating materials, moisture protection materials, light protection materials, gas protection materials, diffusion barrier materials, and dissolution or dispersion enhancing materials, and the retention and dispersion thereof using a wide variety of carrier materials, e.g., pharmaceutically acceptable carriers, adjuvants or excipients, or physiologically active materials, or mixtures thereof.
  • carrier materials e.g., pharmaceutically acceptable carriers, adjuvants or excipients, or physiologically active materials, or mixtures thereof.
  • the present method is particularly advantageous for the precipitation, retention and dispersion of microparticles and nanoparticles of solid or semi-solid material within a carrier material.
  • blends, granulations and partially or fully coated carrier materials, or mixtures thereof, produced by the methods of the present invention are particularly suited for pharmaceutical processing into various pharmaceutical formulations and dosage forms, such as tablets and capsules.
  • Carrier material with good flow characteristics is generally used in the formulation of most solid dosage forms. Its presence in admixture with the drug is therefore an advantage. Blend unifonnity can be achieved even when drug content is very small because drug powder is not handled separately from the excipients and can adhere to excipient particles during its manufacture.
  • the particle size distribution of the processed powder may be close to that of the carrier material itself prior to processing. Flow characteristics of the processed powder may therefore be as good as those of the carrier itself. This reduces difficulties in discharging and in handling the powder in downstream processing.
  • the carrier may be coated with drug substance followed by coating with an encapsulating material. The procedure may be repeated to increase drug loading preferably without causing substantial agglomeration between drug particles to take place.
  • the coatings could also be of a type to offer moisture, light or gas barriers for drugs that are chemically sensitive to water or oxygen or are photosensitive.
  • the coatings could also be of the type that serve as diffusion barriers to control the release of the drug substance from the substrate or as a dissolution or solubility enhancer.
  • This invention is not limited to powders. It may be employed, for example, in blending crystallized microparticles and nanoparticles with larger sized material or for coating of granules, pellets, non-pareils, tablets, capsules or other mixed material. The method can equally be used to form a granulation of the solid or semi-solid material particles with the carrier material.
  • the invention may be used in various ways, including but not limited to:
  • a binder such as polyvinyl pynolidone (PVP) may be present either in admixture with a drug substance in the liquid or gaseous fluid solution or in admixture within the carrier powder bed.
  • PVP polyvinyl pynolidone
  • Coating of a drug substance with a coating material could also be of a type to offer moisture, light or gas barriers for drugs that are chemically sensitive to water or oxygen or are photosensitive.
  • the coatings could also be of the type to serve as diffusion barriers to control the release of the drug substance from the substrate or to enhance its release.
  • FIG. 1 depicts simplified flow diagrams showing two specific embodiments of Modes 1 and 2 of the present invention.
  • Figure 2 is a light microscopy image of polystyrene divinyl benzene micro-bead subjected to supercritical CO 2 at 50° C and 1,000 psig.
  • Figure 3 is a light microscopy image of a polystyrene divinyl benzene micro-bead upon which recrystallized drug substance has been deposited using a method of the present invention wherein the drug substance was recrystallized from a supercritical CO 2 solution.
  • Figure 4 shows the bright field (tungsten) illumination of a group of lactose particles upon which recrystallized drug substance has been deposited using a method of the present invention wherein the drug substance was recrystallized from a supercritical CO 2 solution.
  • Figure 5 shows the UN illumination (high pressure mercury lamp) of a group of lactose particles upon which recrystallized drug substance has been deposited using a method of the present invention wherein the drug substance was recrystallized from a supercritical CO 2 solution.
  • Figure 6 shows the dissolution profile of a drug-lactose mixture obtained by supercritical CO 2 processing of the drug substance using a method of the present invention as compared to the dissolution profile of a drug-lactose mixture obtained by conventional physical mixing of the drug and lactose.
  • Figures 7A to 7C are SEM (Scanning Electron Microscope) photomicrographs of excipient lactose before processing in accordance with the invention. Fig. 7A is at 40 ⁇ magnification; Fig. 7B is at 200x magnification; and Fig. 7C is at 5,000x magnification.
  • Figures 8 A to 8C are SEM photomicrographs of drug solute precipitated by processing out of solution without using a carrier material and without mixing.
  • Fig. 8 A is at 40x magnification
  • Fig. 8B is at 200x magnification
  • Fig. 8C is at 5,000x magnification.
  • Figures 9A to 9C are SEM photomicrographs of a drug/lactose mixture obtained using a method of the present invention wherein the drug substance was precipitated from a sprayed organic solution and blended into and/or coated onto the lactose.
  • the organic solution was sprayed through a nozzle at a distance of about 1 inch above the lactose powder bed.
  • Fig. 9A is at 40x magnification
  • Fig. 9B is at 500x magnification
  • Fig. 9C is at 5,000x magnification
  • Figures 10A to IOC are SEM photomicrographs of a drug/lactose mixture obtained using a method of the present invention wherein the drug substance was precipitated from a non-sprayed organic solution following the introduction of pressurized carbon dioxide, and blended into and/or coated onto the lactose.
  • Fig. 10A is at 40x magnification
  • Fig. 10B is at 200x magnification
  • Fig. 10C is at 5,000x magnification
  • Figure 11 is a photomicrograph of lactose before processing in accordance with the invention.
  • Figures 12 to 15 are SEM photomicrographs of a drug/binder/lactose mixture obtained using a method of the present invention wherein the drug substance and binder were precipitated from a sprayed organic solution and blended into and/or coated onto the lactose.
  • the organic solution was sprayed at a rate of 1.5 mL min through a nozzle located 1 inch above the lactose powder bed, and mixing was at 1000 rpm.
  • Fig. 12 is at 40x magnification
  • Fig. 13 is at 500x magnification
  • Fig. 14 is at 2,000x magnification
  • Fig. 15 is at 5,000x magnification.
  • Figure 16 is a SEM photomicrograph of a drug/binder/lactose mixture obtained using a method of the present invention wherein the drug substance and binder were precipitated from a sprayed organic solution and blended into and/or coated onto the lactose, h this example, the organic solution was sprayed at a rate of 3 mL min through a nozzle located 1 inch above the lactose powder bed, and mixing was at 1000 rpm.
  • Fig. 16 is at 5,000 x magnification.
  • Figures 17 to 19 are SEM photomicrographs of a drug binder/lactose mixture obtained using a method of the present invention wherein the drug substance and binder were precipitated from a sprayed organic solution and blended into and/or coated onto the lactose.
  • the organic solution was sprayed at a rate of 5 mL min through a nozzle located 1 inch above the lactose powder bed, and mixing was at 300 rpm.
  • Fig. 17 is at 500x magnification
  • Fig. 18 is at 5,000x magnification
  • Fig. 19 is at
  • Figure 20 is a graph showing the dissolution profiles of tablets prepared using a drug- lactose mixture obtained according to a method of the present invention as compared to conventionally processed tablets at time zero and at 12 weeks under standard storage conditions of 40 ° C and 75% R-H.
  • Figure 21 is a graph showing the dissolution profiles of tablets prepared using drug- lactose mixtures obtained according to a method of the present invention at three different drug deposition rates (i.e., three different drug solution spray rates).
  • blend is meant a uniform or non-uniform mixture.
  • pressurized gaseous fluid or “supercritical fluid” is meant (1) a fluid or mixture of fluids that is gaseous under atmospheric conditions and that has a moderate critical temperature (i.e., ⁇ 200 °C), or (2) a fluid that has previously found use as a supercritical fluid.
  • gaseous fluids include carbon dioxide nitrous oxide, trifluoromethane, ethane, ethylene, propane, sulfur hexafluoride, propylene, butane, isobutane, pentane, and mixtures thereof.
  • the temperature and pressure of the gaseous or supercritical fluid can be anywhere in the near-critical to supercritical region, e.g., in the range of about 0.8 - 1.6 T c and about 0.8-15 P c where T c and P c are, respectively, the critical temperature in K and the critical pressure of the fluid.
  • microparticles particles having a average particle diameter in the range of about 1 to 500 ⁇ m, preferably in the range of about 1 to 10 ⁇ m.
  • nanoparticles particles having an average particle diameter in the range of about 0.001 to 1 ⁇ m, preferably in the range of about 0.05 to 0.5 ⁇ m.
  • mixed bed with respect to the carrier material is meant a non-fluidized mixture of carrier material, in the absence or presence of precipitated particles of the solid or semi- solid material.
  • a mixed bed of carrier material can be formed, for example, by stirring or agitating the carrier material in the absence or presence of precipitated particles of the solid or semi-solid material.
  • non-fluidized with respect to the carrier material is meant that the carrier material in the mixed bed is not in a gas-suspended fluidized state.
  • the mere stirring or agitating of the carrier material in the bed during the process of the present invention may have the effect of expanding at least some of the carrier material bed, but this is not gas-suspended fluidization of the carrier material.
  • precipitation or “precipitating” mean the process of fonning crystalline or amorphous particles of solute, or mixtures thereof, out of solution. Thus, these terms are intended to include within the context of the present invention the concept of crystallization of dissolved solute out of solution.
  • a mixture of solutes e.g., solid or semi-solid materials
  • the concept of "precipitation” or “precipitating” particles of material in the context of the present invention includes the possibilities that not all the dissolved solutes are precipitated and/or that a solute may precipitate only partially out of solution.
  • the precipitation process of the present invention maybe used to separate certain solid or semi-solid materials.
  • RANS is meant a process whereby solute particles are precipitated from a gaseous fluid solution of the solute by either expanding the solution in a lower pressure region or contacting the solution with an inert gas at the same pressure as the gaseous fluid or at lower pressure.
  • semi-solid is meant a solid material that possesses at least some liquid-type physical characteristics.
  • examples of semi-solid materials include: gels, viscous liquids, oils, surfactants, polymers, waxes, and fatty acids.
  • semi-solid material is meant one or more substances that are semi-solid at ambient or process conditions.
  • a semi-solid material is intended to include the possibility that the semi-solid material is a mixture of different semi-solid materials.
  • solid material is meant one or more substances that are solid at ambient or process conditions.
  • a solid material is intended to include the possibility that the solid material is a mixture of different solid materials.
  • process conditions is meant the specific conditions under which a process of the present invention is run.
  • substantially soluble e.g., with respect to the solubility of the liquid solvent in the gaseous fluid
  • the liquid solvent can be completely solubilized by the gaseous fluid with the exception of residual liquid solvent contamination that may be present on the carrier material particles.
  • substantially insoluble e.g., with respect to the solubility of the solid or semi-solid material in the gaseous fluid in Mode 2, is meant that under selected processing conditions the solid or semi-solid material should be no more than about 50% by weight soluble, preferably no more than about 25% by weight soluble, more preferably no more than about 5% by weight soluble in the gaseous fluid. It is preferable that under the selected processing conditions the solid or semi-solid material is essentially completely insoluble in the gaseous fluid.
  • Mode 1 is meant a process according to the present invention using steps (a)(1) and (b)(1) described above wherein a solid or semi-solid material is precipitated out of a gaseous fluid solution.
  • Module 2 is meant a process according to the present invention using steps (a)(2) and (b)(2) described above wherein a solid or semi-solid material is precipitated out of a liquid solution.
  • the supercritical or organic solution is introduced as a spray or a jet directly into a mixed bed of a carrier material, e.g., a drug substance or a earner material such as lactose, starch or dicalcium phosphate.
  • a carrier material e.g., a drug substance or a earner material such as lactose, starch or dicalcium phosphate.
  • the orifice producing the spray or jet is located within or close to the bed of carrier particles so that it rapidly contacts the carrier particles.
  • mechanical mixing of the carrier material is preferred because it causes the spray to continuously come in contact with different carrier particles, thereby uniformly distributing the precipitated solute throughout the mixed powder and minimizing contact among solute particles. Mechanical mixing also imparts shear to the particles which aids in spreading the spray droplets or formed particles across the surface of the carrier material.
  • the carrier material is mechanically mixed during the process. Agglomeration may be reduced by mechanical stirring and blending with carrier material which imparts some shear that serves to de- agglomerate particles and causes higher mass transfer rates of the liquid solvent to the fluid phase which reduces contact time among wet particles.
  • Applicants have unexpectedly discovered that powders of carrier material with good flow, handling and compression properties can be used to trap solute material precipitated (e.g. recrystallized) using SCFs to produce powders with similarly good properties.
  • the ability of carrier material to retain recrystallized material can overcome major difficulties with SCF processing.
  • the carrier can therefore act as a medium for adhesion of recrystallized particles, as a medium for filtering recrystallized particles out of the fluid mixture and as a medium for dispersing the recrystallized particles.
  • a high throughput is also achieved because the need for a flow restrictive filter is alleviated since most fine microparticles and nanoparticles are retained in the canier material.
  • Another particular advantage of the process of the present invention is that it can be used to process either solid or semi-solid solute material from either liquid or supercritical solutions. Solid and semi-solid solute particles are rapidly dispersed within carrier material as they are formed thereby minimizing their agglomeration with like solute particles. It should be noted that although mechanical mixing introduces shear to facilitate solute distribution and deagglomeration, agglomeration may also be enhanced if desired by controlling processing parameters such as the rate of addition of a binder solution into the pressurized gaseous fluid. Therefore, the process may be used to cause adherance of recrystallized particles to carrier particles, granulate such particles, or improve their flow properties.
  • Steps (a)(1) and (b)(1) of the present inventive method are analogous to the RESS technique of precipitating gaseous fluid (e.g. SCF) soluble material from a pressurized gaseous fluid solution by introducing the solution into a region of lower pressure or a region containing an inert gas.
  • gaseous fluid e.g. SCF
  • Such techniques are described, for example, in the following U.S. Patents, each of which is incorporated herein by reference in its entirety: U.S. 4,582,731 and U.S. 4,734,451.
  • Based on the RESS technique known in the art one skilled in the art can readily adapt and employ the RESS method to the process of the present invention.
  • any of the conventional conditions i.e., temperature, pressure, precipitation vessels, nozzle variations, etc
  • any of the conventional conditions i.e., temperature, pressure, precipitation vessels, nozzle variations, etc
  • steps (a)(1) and (b)(1) of the present inventive method can be employed in steps (a)(1) and (b)(1) of the present inventive method.
  • the pressurized gaseous fluid solution temperature is preferably higher than T c of the gaseous fluid, more preferably in the range of about 1 to 1.6 x T c ; the pressure of the pressurized gaseous fluid solution is preferably higher that P c , more preferably in the range of about 1 to 15 x P c ; Pressure and temperature in the particle collection vessel or region are preferably ambient or close to ambient conditions.
  • the gaseous fluid is preferably CO 2 , nitrous oxide, ethane, ethylene or propane, more preferably CO 2 . Gaseous fluids may be recycled to the process if desired.
  • a pressurized gaseous fluid solution of a solute is expanded onto or into a mixed bed of carrier particles in a particle collection vessel held at a lower pressure.
  • the gaseous fluid enters the vessel from a location within the earner bed, or slightly above the upper surface, or from underneath the earner particle bed and exits the vessel though an alternate opening at the bottom, side or top of the vessel.
  • the gaseous fluid preferably enters the vessel from a location slightly above the upper surface of the carrier particle bed and exits through an opening at the bottom of the vessel. This will help to ensure that the precipitated particles contact the carrier particles intimately prior to exiting the particle collection vessel.
  • the bed of carrier particles is preferably stirred using one or more rotating mixing devices. Speeds in the range of 0 to 5,000 RPM, preferably 50 to 3,000 RPM, may be used.
  • Steps (a)(2) and (b)(2) of the present inventive method are similar to the SAS and GAS techniques of precipitating gaseous fluid insoluble material from a solution of the material in a liquid solvent (e.g., an organic solvent or a mixture of an organic solvent and water) by either introducing the solution into a region containing a pressurized gaseous fluid in which said liquid solvent is soluble but the dissolved solute is substantially insoluble, or by introducing the solution into a region into which the pressurized gaseous fluid is subsequently added to cause the precipitation of the gaseous fluid insoluble material.
  • a liquid solvent e.g., an organic solvent or a mixture of an organic solvent and water
  • any of the conventional conditions i.e., temperature, pressure, fluid flow rates, precipitation vessels, nozzle variations, etc
  • any of the conventional conditions i.e., temperature, pressure, fluid flow rates, precipitation vessels, nozzle variations, etc
  • any of the conventional conditions i.e., temperature, pressure, fluid flow rate, precipitation vessels, nozzle variations, etc
  • steps (a)(2) and (b)(2) of the present inventive method can be employed in steps (a)(2) and (b)(2) of the present inventive method.
  • Prefened conditions are as follows:
  • the temperature in the precipitation vessel is preferably higher than the critical temperature of the gaseous fluid, more preferably in the range of about 1 to 1.6 x T c
  • the pressure in the precipitation vessel is preferably higher than the critical pressure of the gaseous fluid, more preferably in the range of about 1 to 15 x P c .
  • the ratio of liquid solution flow rate to gaseous fluid flow rate should preferably be in the range of about 0.001 to 0.1, more preferably in the range of about 0.01 to 0.05.
  • Pressure, temperature, gaseous fluid flow rate and liquid solution flow rate should preferably be such that the fluid mixture in the precipitation vessel is homogeneous.
  • the bed of carrier particles is preferably stined using one or more rotating mixing devices. Speeds in the range of 50 to 3,000 RPM are prefened.
  • the nozzle through which the liquid solution may be introduced into the precipitation vessel can be, for example, an orifice nozzle, a capillary nozzle, an ultrasonic nozzle, or a coaxial nozzle, e.g. the type employed in a SEDS method, as discussed previously.
  • the liquid solution may alternatively be introduced through a regular flow line or orifice with no spray atomization capability.
  • the solution may be added very quickly or mixed with the carrier material before vessel closure, pressurization, and flow of the gaseous fluid begins.
  • the pressurized gaseous fluid is preferably pumped into the vessel from above the upper surface where the carrier powder bed is at rest.
  • the liquid solution is preferably introduced into the vessel from a level below or slightly above the upper surface of the carrier powder bed at rest. Since the liquid is sprayed directly onto or into the powder bed, it is believed that at least some particle formation may take place by SFE of the solvent from droplets of solution on the carrier particles. Specifically, droplets of the liquid solution may make contact with and adhere to the carrier material and precipitation of the solid or semi-solid material would then result from the extraction of the liquid solvent from said droplets into said gaseous fluid.
  • the precipitated particles would be fonned from a droplet of solution adhered to the carrier particle and may result in the formation of a thin coating of the precipitated material on the carrier particle; the selection of a good wetting solvent would therefore serve to enhance adhesion and surface distribution of the solute on the carrier particles.
  • the gaseous fluid may serve to dissolve in and expand the liquid solution to a level where the solid or semi-solid material is no longer soluble in the mixture of gaseous fluid-liquid solvent, thereby effecting precipitation.
  • particles precipitated from the droplets can form either particles loosely adhered to carrier particles, a coating on carrier particles or a granulation, or mixtures thereof.
  • a change in the location of the opening or orifice producing the spray can be used to change the characteristics of the resulting powder. The closer the orifice is to the powder bed, the wetter the carrier particles, and the greater the potential for coating or granulating the powder mixture.
  • This method of the invention is ideally suited for rapid granulation of pharmaceutical formulations. In-situ particle formation and granulation or coating can eliminate several downstream handling and processing steps and can therefore reduce health risks and production costs.
  • the introduced solution and resulting precipitated particles produced via Mode 1 (steps (a)(1) and (b)(1)) or Mode 2 (steps (a)(2) and (b)(2)) discussed previously are directed onto or into the carrier material bed such that there is retention of the precipitated particles in the carrier material.
  • This is accomplished by introducing the gaseous fluid solution or liquid solvent solution of (a)(1) or (a)(2) into the appropriate region as specified in steps (b)(1) or (b)(2), and onto or into the mixed bed of carrier material such that at least some of the particles precipitating out of the gaseous fluid or liquid solvent solution are retained by the carrier material.
  • this can result in the production of a blend of the solid or semi-solid precipitated material with carrier material, a granulation of the solid or semi-solid precipitated material with carrier material, or carrier material partially or fully coated with carrier material, or mixtures thereof.
  • the precipitation vessel can be partially or fully loaded with carrier material.
  • the process conditions within the precipitation vessel itself e.g., temperature, pressure, fluid flow rates
  • pressure and temperature in the precipitation vessel or region are preferably ambient or close to ambient conditions.
  • the bed of carrier particles is preferably stined using one or more rotating mixing devices. Speeds in the range of 0 to 5,000 RPM, e.g., 50 to 3,000 RPM, are prefened.
  • prefened processing conditions are:
  • the temperature in the precipitation vessel or region is preferably higher than the critical temperature of the gaseous fluid, more preferably in the range of about 1 to 1.6 x T c
  • pressure is preferably higher than the critical pressure of the gaseous fluid, more preferably in the range of about 1 to 15 x P c .
  • the ratio of liquid solution flow rate to gaseous fluid flow rate should preferably be in the range of about 0.001 to 0.1, more preferably in the range of about 0.01 to 0.05.
  • Pressure, temperature, gaseous fluid flow rate and liquid solution flow rate should preferably be such that the fluid mixture in the vessel is homogeneous.
  • the carrier material bed is maintained in a mixed state (e.g. by continuous stirring, agitating, or mixing by any other means) during the precipitation of the solid or semi-solid material to disperse it throughout the bed of carrier material.
  • a mixed state e.g. by continuous stirring, agitating, or mixing by any other means
  • the carrier bed is maintained in a mixed state at least during steps (c) and (d) of the inventive method.
  • Stirring of a carrier material powder can be accomplished easily, inespective of particle size distribution and its change throughout the process.
  • Mechanical stining may be effected using any of a number of mixing device designs, including pitched, curved or flat blade turbines, anchors, impellers, propellers, dispersers, homogenizers, and helical ribbons.
  • the bed of carrier particles is preferably stined using one or more rotating mixing devices. Speeds in the range of 50 to 3,000 RPM are prefened.
  • the distance between the mixed bed of carrier material and the opening or orifice through which the gaseous fluid solution or liquid solution is introduced into the precipitation chamber will affect the characteristics and quality of the mixture obtained.
  • One skilled in the art can easily adjust this distance as well as pressure, temperature and liquid and fluid flow rates to obtain the desired product, be it a blend, granulation or coated carrier material or mixtures thereof, while preferably preventing substantial agglomeration among the precipitated particles.
  • the precipitated particles are directed onto or into the mixed bed of carrier material by introducing the gaseous fluid solution or the liquid solution through an opening located above and close to the surface of the bed of mixed carrier material or through an opening located within the bed of mixed carrier material.
  • the precipitated particles are directed onto or into the mixed bed of carrier material through an opening located at a distance of at least about 0 to 12 inches, preferably at least about 2 inches, from the surface of the bed of mixed carrier material or through an opening located within the bed of mixed carrier material.
  • the surface of the bed may increase over time as more solid or semi-solid precipitated material, for example, drug, coating, and/or binder material is added to the carrier bed.
  • the final product of this inventive method can either be a blend of solid or semi-solid material particles with carrier material, a granulation of solid or semi-solid material particles with carrier material, or carrier material partially or fully coated with solid or semi-solid material particles.
  • the blends, granulations, partially or fully coated carrier materials, or mixtures thereof, produced by the methods according to the present invention can be processed into various pharmaceutical formulations and dosage forms, such as tablets and capsules, by conventional techniques.
  • the product can be a uniform or non-uniform mixture of carrier material, discrete particles of solid or semi- solid material, and carrier material having solid or semi-solid material loosely adhered thereto.
  • the inventive method can be repeated one or more times on the initially coated carrier material using the same or different coating materials.
  • a coated carrier material produced in step (d) can be further coated by performing a coating method of the present invention one or more times on said coated carrier material, wherein the solid or semi-solid material used in the initial and subsequent coating methods may be the same or different during each coating method.
  • the carrier material may be initially coated with a drug substance followed by coating with an encapsulating material and the entire process can be repeated to increase drug loading.
  • the drug substance can also be coated with a moisture, light or gas protecting material or a diffusion barrier material, or dissolution or dispersion enhancing material, or combinations thereof in different coating layers. A wide number of variations and applications of this coating technique are possible.
  • a binder such as PVP may be present either in admixture with a drug substance in the liquid or pressurized gaseous fluid solution or in admixture within the carrier powder bed.
  • the gaseous fluid can flow out of the vessel after contact with the powder bed. It is prefened that the gaseous fluid flow through a large fraction of the powder bed prior to exiting the vessel through a filter sized small enough to retain at least the carrier particles. It is therefore prefened that the solute-depleted fluid mixture flow out the precipitation vessel through a filter located at the bottom of the carrier bed. This should ensure a high particle retention efficiency and more uniform rate of mass transfer of solvent into the gaseous fluid in the case of Mode 2.
  • stirring may be optional during the process, especially in Mode 1 of the invention. Stirring may be required if a uniform distribution of recrystallized material in the carrier material is desired.
  • This prefened mode is made possible by the relatively low viscosity and high diffusivity of gaseous fluids and gases and the high particle retention efficiency of the carrier material.
  • the liquid solvent-gaseous fluid mixture flows out of the precipitation vessel and is then expanded at a reduced pressure level to separate the gaseous fluid from the liquid solvent.
  • the liquid solvent can be recovered in a cold trap and the gaseous fluid vented or recycled into the process.
  • Figure 1 depicts flow diagrams showing two specific embodiments of Modes 1 and 2 of the present inventive method.
  • a variety of solid or semi-solid materials, gaseous fluids, liquid solvents, and carrier materials can be employed in the present inventive method to produce a variety of types of products.
  • the solid or semi-solid material that is precipitated can be selected from physiologically active materials, such as a chemical pharmaceuticals, and agricultural materials such as herbicides and fertilizers.
  • the solid or semi-solid material may also be an industrial chemical, foodstuff, fine chemical, cosmetic chemical, photographic chemical, dye, paint, polymer, an encapsulating material, a moisture protection material, a light protection material, a gas protection material, a diffusion barrier material or a dissolution or dispersion enhancing material, hi a prefened embodiment the solid or semi-solid material is a physiologically active material.
  • physiologically active materials such as a chemical pharmaceuticals, and agricultural materials such as herbicides and fertilizers.
  • the solid or semi-solid material may also be an industrial chemical, foodstuff, fine chemical, cosmetic chemical, photographic chemical, dye, paint, polymer, an encapsulating material, a moisture protection material, a light protection material, a gas protection material, a diffusion barrier material or a dissolution or dispersion enhancing material, hi a prefened embodiment the
  • the physiologically active material can be selected from Ipratropium bromide, tiotropium bromide, oxytropium bromide, tipranavir, albuterol, albuterol sulfate, clenbuterol, fenoterol, beclomethasone diproprionate, insulin, amino acids, analgesics, anti-cancer agents, antimicrobial agents, antiviral agents, antifungals, antibiotics, nucleotides, amino acids, peptides, proteins, immune suppressants, thrombolytics, anticoagulants, central nervous system stimulants, decongestants, diuretic vasodilators, antipsychotics, neurotransmitters, sedatives, hormones, anesthetics, anti-inflammatories, antioxidants, antihistamines, vitamins, minerals and other physiologically active materials known to the art; the encapsulating material can be selected from the above physiologically active materials, gels, waxes, polymers, and fatty acids;
  • Dissolution or dispersion enhancers can be selected from surfactants (e.g., tween), or wetting agents (e.g., sis, sds), solubilizing agents, dispersing agents, carrier surface modification materials such as polymers that promote adhesion (PVP, PVA, cellulose), or silicon dioxide, etc.
  • surfactants e.g., tween
  • wetting agents e.g., sis, sds
  • solubilizing agents e.g., solubilizing agents
  • dispersing agents e.g., solubilizing agents, dispersing agents, carrier surface modification materials such as polymers that promote adhesion (PVP, PVA, cellulose), or silicon dioxide, etc.
  • PVP polymers that promote adhesion
  • PVA polymers that promote adhesion
  • silicon dioxide silicon dioxide
  • the precipitated particles of solid or semi-solid material that are produced in the inventive process may comprise microparticles or nanoparticles of solid or semi-solid material, or mixtures thereof.
  • the process is particularly suited to the efficient retention of such small particles in the carrier material.
  • the gaseous fluid employed in the inventive method includes, for example, any gaseous fluid that is commonly employed in conventional supercritical fluid processes such as SFE, RESS and SAS.
  • suitable gaseous fluids include carbon dioxide, nitrous oxide, trifluoromethane, ethane, ethylene, propane, sulfur hexafluoride, propylene, butane, isobutane, pentane, and mixtures thereof.
  • the liquid solvent that may be employed in the inventive method includes, for example, water or any organic liquid solvent that may be employed in conventional SAS processes.
  • organic solvents include aliphatic alcohols, such as ethanol, methanol, propanol and isopropanol, acetone, dichloromethane, ethyl acetate, dimethyl sulfoxide, polymers, surface wetting enhancer(s) such as surfactants, and mixtures thereof. Water may also be present in admixture with any of the above organic solvents.
  • the carrier material used in the inventive method can be selected from any pharmaceutically acceptable carrier, adjuvant or excipient, or a physiologically active material, or mixtures thereof.
  • pharmaceutically acceptable carriers, adjuvant or excipient that can be used include lactose, including hydrated forms thereof, dextrose, sucrose, starch, polyethylene glycol, PVP, polyvinyl alcohol, lecithin, microcrystalline cellulose, hydroxypropyl methyl cellulose, calcium carbonate, dicalcium phosphate, calcium triphosphate, magnesium carbonate and sodium chloride.
  • physiologically active materials that can be used as carrier materials include Ipratropium bromide (LB.), tiotropium bromide, oxytropium bromide, albuterol, albuterol sulfate, clenbuterol, fenoterol, beclomethasone diproprionate, insulin, amino acids, analgesics, anti-cancer agents, antimicrobial agents, antiviral agents, antifungals, antibiotics, nucleotides, amino acids, peptides, proteins, immune suppressants, thrombolytics, anticoagulants, central nervous system stimulants, decongestants, diuretic vasodilators, antipsychotics, neurotransmitters, sedatives, hormones, anesthetics, anti-inflammatories antioxidants, antihistamines, vitamins, minerals.
  • Ipratropium bromide LB.
  • tiotropium bromide tiotropium bromide
  • oxytropium bromide albuterol
  • the canier material can also take a variety of forms depending on the desired product such as, for example, a powder, granulated powder, tablets, capsules or caplets.
  • the carrier material is a powder it can take the form of microparticles or nanoparticles of carrier material, or mixtures thereof.
  • the carrier material is a powder comprising microparticles and/or nanoparticles of pharmaceutically acceptable carrier, adjuvant or excipient, or microparticles and/or nanoparticles of a physiologically active material, or mixtures thereof.
  • Mode 1 of the inventive process is directed to a method for particle precipitation, retention and dispersion in carrier material comprising:
  • step (b) precipitating microparticles and/or nanoparticles of the physiologically active material out of the gaseous fluid solution produced in step (a) by introducing the solution through an orifice into a lower pressure region or into a region containing an inert gas;
  • step (c) directing the introduced solution and resulting microparticles and/or nanoparticles produced in step (b) onto or into a mixed bed of powdered carrier material, said powdered carrier material comprising microparticles and/or nanoparticles of a pharmaceutically acceptable carrier, adjuvant or excipient; and
  • step (d) retaining at least some of the microparticles and/or nanoparticles produced in step (b) in the powdered carrier material to produce a blend of the physiologically active material particles and carrier material, a granulation of the physiologically active material particles with carrier material, carrier material partially or fully coated with the physiologically active material, or mixtures thereof.
  • Additional embodiments are directed to the Mode 1 method set forth above wherein: the pressurized gaseous fluid is carbon dioxide; the region into which the gaseous fluid solution is introduced is a lower pressure region; the orifice is located above the upper surface of the mixed bed of carrier material when the mixed bed is at rest or within the mixed bed when the mixed bed is at rest; the carrier material is lactose; the mixed bed of carrier material is maintained in a mixed state during steps (c) and (d), e.g, by mixing at a speed of about 300 to 1,000 RPM; and/or the product of step (d) is at least some powdered carrier material partially or fully coated with the physiologically active material.
  • the pressurized gaseous fluid is carbon dioxide
  • the region into which the gaseous fluid solution is introduced is a lower pressure region
  • the orifice is located above the upper surface of the mixed bed of carrier material when the mixed bed is at rest or within the mixed bed when the mixed bed is at rest
  • the carrier material is lactose
  • the mixed bed of carrier material is
  • Mode 2 of the inventive process is directed to a method for particle precipitation, retention and dispersion in carrier material comprising:
  • step (a) dissolving a solid or semi-solid physiologically active material in a liquid solvent, thereby forming a solution comprising a liquid solvent and a dissolved physiologically active material
  • step (b) precipitating microparticles and/or nanoparticles of the physiologically active material out of the liquid solution produced in step (a) by introducing the solution through an orifice into either: (1) a region containing pressurized gaseous fluid in which said liquid solvent is substantially soluble but said physiologically active material is substantially insoluble, or (2) a region into which said pressurized gaseous fluid is subsequently introduced to cause the solubilization of the liquid solvent into the pressurized gaseous fluid and the precipitation of said microparticles and/or nanoparticles;
  • step (c) directing the introduced solution and resulting microparticles and/or nanoparticles produced in step (b) onto or into a mixed bed of powdered carrier material, said powdered carrier material comprising microparticles and/or nanoparticles of a pharmaceutically acceptable canier, adjuvant or excipient; and
  • step (d) retaining at least some of the microparticles and/or nanoparticles produced in step (b) in the powdered carrier material to produce a blend of the physiologically active material particles and carrier material, a granulation of the physiologically active material particles with carrier material, carrier material partially or fully coated with physiologically active material, or mixtures thereof.
  • the liquid solvent is a liquid organic solvent, for example, an aliphatic alcohol solvent
  • the gaseous fluid is carbon dioxide
  • the liquid solution is sprayed through an orifice into a region containing a pressurized gaseous fluid, wherein the orifice is located above the upper surface of the mixed bed of carrier material when the mixed bed is at rest or is located within the mixed bed when the mixed bed is at rest; the mixed bed of carrier material is maintained in a mixed state during steps (c) and (d); and/or the product of step (d) is at least some powdered carrier material partially or fully coated with the physiologically active material.
  • a further embodiment is directed to the Mode 2 methods set forth above wherein during steps (b) and (c) droplets of the liquid solution make contact with the powdered carrier material and precipitation of the physiologically active material results from the extraction of the liquid solvent from said droplets into the pressurized gaseous fluid.
  • a solid or semi-solid physiologically active material and a solid or semi-solid binder material are both dissolved in the liquid solution in step (a);
  • the liquid solvent is methanol or ethanol;
  • the carrier material is lactose; and/or the mixed bed of carrier material is maintained in a mixed state by mixing at a speed of about 20 to 1,000 RPM, preferably about 300 to 1,000 RPM
  • the objective of these examples is to demonstrate that the present invention can be used to deposit solutes from organic solutions or gaseous fluids or mixtures thereof to form blends of a solute material on a carrier wherein the solute is distributed mostly on the carrier as either discrete particles, a coating around the carrier particles, or a mixture of a coating and discrete particles.
  • Example 1 Recrvstallization of a drug substance from supercritical CO, and coating of polymeric micro-beads
  • Five (5) grams of a drug substance was mixed with an inert material (diatomaceous earth) and charged into a 1 liter vessel.
  • Supercritical CO 2 at 80 °C and 310 bar was then used to extract and solubilize the drug substance.
  • the drug-laden effluent CO 2 stream was then expanded to a lower pressure through a 75 ⁇ m orifice nozzle located in a 300 mL mixing vessel containing 25 grams of a white powder that consists of polystyrene divinyl benzene beads with a particle size in the range of 40-80 ⁇ m.
  • the powder was mixed at 1,000 RPM using two 4-blade pitched radial impellers attached to the drive shaft.
  • the bottom impeller was located near the bottom of the vessel.
  • the nozzle lip was set close to the top of the powder bed so that the drug substance precipitated as microparticles and nanoparticles and rapidly mixed with the powder.
  • Mixing vessel temperature and pressure were 40-50 °C and up to 1,000 psig.
  • Effluent CO 2 passed through a 60 ⁇ m filter frit and was then vented.
  • FIG. 2 shows a light microscopy image of a bead subjected to supercritical CO 2 at 50 °C and 1,000 psig.
  • Polaroid software version 1.1 was used to view images on the microscope (Olympus BH2 Polarized Light Microscope and Polaroid DMC le). The bead appears to be spherical and is not damaged by high-pressure CO 2 .
  • Figure 3 shows a light microscopy image of a bead which was treated according to the invention. The surface appears to be covered with extraneous material and a coating appears to be deposited on its surface. Drug material appeared to be adhered to the beads.
  • Example 2 RecrystaUization of a drug substance from supercritical CO ? and coating of lactose monohydrate
  • the beads used in the above example were replaced with lactose monohydrate, a widely used excipient material in tablet formulations.
  • the processed powder contained about 10% drug, bore a yellowish color and appeared to have flow properties similar to those of unprocessed lactose.
  • Light Microcopy (or bright field microscopy) and scanning electron microscopy did not provide evidence on the location of the drug substance within the processed powder. Because the drug substance is brightly fluorescent and lactose is not fluorescent, fluorescence microscopy was used to demonstrate that drug particles are fully associated with lactose particles.
  • Samples were prepared from processed dry powders by sprinkling a small amount of powder onto a glass microscope slide, adding 3 drops of non-fluorescent immersion oil and covering with a number 1.5 glass cover slip. Preparations were kept for less than one day at room temperature and were protected from light except when being examined in the microscope.
  • the microscope was a Nikon Microphot with a band pass filter tuned for fluorescence in Isothiocyanate emission. Samples were examined in bright field (tungsten) and UN illumination (high pressure mercury vapor lamp), with 20X, 40X and 60X objectives. Magnification calibration was performed with a Don Santo stage micrometer (1mm divided into 10 micrometer intervals). Images were captured with a SNMicro digital camera.
  • Figure 4 shows in bright field illumination a group of lactose particles treated with the drug substance. A typical appearance of a group of particles viewed in bright field illumination is observed.
  • Figure 5 shows the same field illuminated with UV light. Each particle is fluorescent indicating that each lactose particle is associated with the drug substance. This technique can therefore be used to produce intimately and unifonnly mixed powders.
  • Dissolution of the above drug-lactose mixture was then conducted using the standard stined basket method and compared to the dissolution of a conventional physical powder mixture of drug-lactose using the same dissolution method.
  • the two drug- lactose mixtures that were analyzed had the same drug/lactose ratio.
  • the dissolution profiles, see Figure 6, show that supercritical fluid-processed material exhibits faster dissolution, with sometimes as much as double the amount drag release per time period.
  • Example 3 Precipitation of a drug substance from a sprayed organic solution and blending it into and/or coating it onto lactose particles with the nozzle above the bed.
  • a mass of 25 grams of lactose (approximate size: 99% less than 63 ⁇ m) was charged into a 300 mL vessel immersed in an isothermal (50 °C) water bath.
  • the vessel was closed, mixing was started at 1000 rpm and CO 2 flow through the vessel was then established.
  • the desired pressure of 1,500 psig about 95 L of a solution of 25 mg/mL of a drag substance in methanol was sprayed through a 75 ⁇ m nozzle for about 1 hour at 1.5 mL/min.
  • the nozzle tip was set at about 4 inches above the powder bed at rest.
  • the solution rapidly mixed with supercritical CO 2 causing the CO 2 -insoluble drug to rapidly crystallize and blend within the bed.
  • Effluent solvent- supercritical CO 2 mixture passed through a 60 ⁇ m filter and then was expanded down to atmospheric level. Solvent was recovered in a cold trap and gaseous CO 2 was vented to the atmosphere. Effluent near-atmospheric pressure CO 2 flow rate was about 45 standard liters per minute throughout this period.
  • Example 4 Precipitation of a drag substance from a sprayed organic solution and blending it into and/or coating it onto lactose particles with the nozzle in or near the bed.
  • This example was a repeat of Example 3 except the nozzle was lowered to about linch above the powder bed at rest. As expected, during stirring the bed covered the nozzle.
  • FIGS 7A to 7C show SEM photomicrographs of excipient lactose before processing (Fig. 7A is at 40x magnification; Fig. 7B is at 200x magnification; and Fig. 7C is at 5,000x magnification).
  • Figures 8 A to 8C show SEM photomicrographs of the drug solute precipitated by processing out of solution without lactose and stining (Fig.
  • FIG. 8 A is at 40x magnification; Fig. 8B is at 200x magnification; and Fig. 8C is at 5,000x magnification).
  • the drug substance can be seen to crystallize in the shape of acicular, elongated needle like particles.
  • Figures 9 A to 9C show SEM photomicrographs of the drug-lactose mixture obtained by the process of Example 4 (Fig. 9A is at 40x magnification; Fig. 9B is at 500x magnification; and Fig. 9C is at 5,000x magnification).
  • Fig. 9A is at 40x magnification
  • Fig. 9B is at 500x magnification
  • Fig. 9C is at 5,000x magnification
  • the drag appears as discrete particles, as particles adhered to lactose particles, and/or as particles coated onto the lactose
  • Example 5 Precipitation of a drag substance from a non-sprayed organic solution and blending it into and/or coating it onto lactose particles.
  • Solvent was recovered in a cold trap and gaseous CO 2 was vented to the atmosphere.
  • the gaseous fluid served to dissolve in and expand the organic solution to a level where the drug substance was no longer soluble in the mixture of gaseous fluid-organic solvent.
  • Example 6 Precipitation of a drag substance from a non-sprayed organic solution and blending into and/or coating of lactose canier particles using reduced solvent, increase pressure, and an initial settling step.
  • a mass of 25 grams of lactose (approximate size: 99% less than 63 ⁇ m) was charged into a 300 mL vessel immersed in an isothermal (50 °C) water bath.
  • a solution of 50mL containing 50 mg/mL of a drag substance in methanol was added to the carrier in the vessel.
  • the vessel was closed, mixing started at 1000 rpm, and CO 2 slowly added to the vessel until the desired pressure of 2,000 psig was established.
  • FIGS 10A to 10C show SEM photomicrographs of the drug-lactose mixture obtained by the process of Example5 (Fig. 10A is at 40x magnification; Fig. 10B is at 200x magnification; and Fig. 10C is at 5,000x magnification). These photomicrographs show that small elongated particles of the drug substance are uniformly distributed throughout the mixture in various sized clusters. Lactose particles appear to be of a size similar to that of drag particles. The exact reason why large lactose particles are no longer observed is not known.
  • Example 7 Precipitation of a drag substance from a sprayed organic solution containinp; a binder and blending it into and/or coating it onto lactose particles with good flow properties.
  • a mass of 25 grams of lactose (approximate size: 75% less than 100 ⁇ m) having excellent flow was charged into a 300 mL vessel immersed in an isothermal (50 °C) water bath. The vessel was closed, mixing was started at 1000 rpm and CO 2 flow through the vessel was then established.
  • Example 8 Precipitation of a drug substance from a sprayed organic solution containing a binder and blending it into and/or coating it onto lactose particles with good flow properties at a medium rate of deposition.
  • Example 7 This example is similar to Example 7, except that the spray rate was 3 mL/min. The 200 mL of a solution addition was complete in about 1 1/4 hours. The mixture was dried for an additional 1 % hours.
  • Example 9 Precipitation of a drug substance from a sprayed organic solution containing a binder and blending it into and/or coating it onto lactose particles with good flow properties at a high rate of deposition.
  • Example 7 This example is similar to Example 7, except that the stiner speed was reduced throughout the run to 300 rpm, and the spray rate was 5 mL/min. The 200 mL of a solution addition was complete in about 45 minutes. The mixture was dried for an additional 1 % hours.
  • Figures 13 (500x) and 14 (2,000x) show that the deposition has taken place as both elongated particles and as droplets of binder and drug materials, which after extraction of the solvent left fused masses of solid. The droplets, sometimes as clusters, also contain lactose and drag fragments.
  • Figure 15 (5,000x) shows that the precipitated microparticles and/or nanoparticles are a porous deposition with various degrees of binder material present.
  • FIG. 20 shows comparative dissolution profiles of tablets prepared using a drug-lactose mixture obtained by supercritical CO 2 processing according to a method of the present invention (Example 7) as compared to conventionally processed tablets at time zero and at 12 weeks under standard storage conditions of 40 ° C and 75% RH.
  • the tablets containing the supercritical fluid processed material had faster dissolution initially and after 12 weeks under storage conditions.
  • Figure 21 shows a comparison of the dissolution rates of tablets prepared using drug-lactose mixtures obtained by processing according to Examples 7, 8 and 9.
  • Figure 21 shows a similarity in profiles indicating good process control at different spray rates of drug solution.
  • the slightly higher dissolution rate for the 5 ml/minute spray rate is expected as the SEM photomicrographs show greater contact of drag and binder which can act as a dissolution enhancer. It is believed that at the higher spray rate of 5 ml/minute, the solution first deposits on the carrier particles and precipitation may take place by SFE of the solvent spread over the carrier particles.

Landscapes

  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Powder Metallurgy (AREA)
  • Physical Or Chemical Processes And Apparatus (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé de précipitation de petites particules, de rétention et de dispersion d'un matériau solide ou semi-solide sur ou dans un matériau porteur. Dans ce procédé, des particules de soluté sont précipitées à partir d'une solution de fluide gazeux sous pression ou d'une solution liquide et ces particules sont efficacement retenues et dispersée dans un matériau porteur. On peut avantageusement utiliser cette technique dans un traitement pharmaceutique pour produire un mélange de particules de matériau solide ou semi-solide et un matériau porteur, une granulation de ces particules de matériau solide ou semi-solide avec un matériau porteur, un matériau porteur partiellement ou complètement revêtu de ces particules de matériau solide ou semi-solide ou d'un mélange de celles-ci.
PCT/US2002/032303 2001-10-10 2002-10-10 Traitement de poudre avec des fluides gazeux sous pression WO2003030871A1 (fr)

Priority Applications (13)

Application Number Priority Date Filing Date Title
EP02800989A EP1435916B1 (fr) 2001-10-10 2002-10-10 Traitement de poudre avec des fluides gazeux sous pression
JP2003533904A JP2005511521A (ja) 2001-10-10 2002-10-10 加圧ガス状流体による粉末処理
MXPA04003321A MXPA04003321A (es) 2001-10-10 2002-10-10 Procesado de polvo con fluidos gaseosos presurizados.
CA2462338A CA2462338C (fr) 2001-10-10 2002-10-10 Traitement de poudre avec des fluides gazeux sous pression
BR0213155-2A BR0213155A (pt) 2001-10-10 2002-10-10 Processamento de pó com fluidos gasosos pressurizados
DE60211004T DE60211004T2 (de) 2001-10-10 2002-10-10 Pulververarbeitung mit unter druck stehenden gasförmigen fluids
NZ532759A NZ532759A (en) 2001-10-10 2002-10-10 Powder processing with pressurized gaseous fluids
IL16093102A IL160931A0 (en) 2001-10-10 2002-10-10 Powder processing with pressurized gaseous fluids
EA200400483A EA006064B1 (ru) 2001-10-10 2002-10-10 Способ обработки порошков сжиженными газами
AU2002334935A AU2002334935B2 (en) 2001-10-10 2002-10-10 Powder processing with pressurized gaseous fluids
YU29104A RS29104A (en) 2001-10-10 2002-10-10 Powder processing with pressurized gaseous fluids
HR20040334A HRP20040334A2 (en) 2001-10-10 2004-04-08 Powder processing with pressurized gaseous fluids
HK05102734A HK1069994A1 (en) 2001-10-10 2005-04-01 Powder processing with pressurized gaseous fluids

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US32830101P 2001-10-10 2001-10-10
US60/328,301 2001-10-10

Publications (1)

Publication Number Publication Date
WO2003030871A1 true WO2003030871A1 (fr) 2003-04-17

Family

ID=23280401

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2002/032303 WO2003030871A1 (fr) 2001-10-10 2002-10-10 Traitement de poudre avec des fluides gazeux sous pression

Country Status (23)

Country Link
US (1) US6858166B2 (fr)
EP (1) EP1435916B1 (fr)
JP (2) JP2005511521A (fr)
KR (1) KR20050035146A (fr)
CN (1) CN1273113C (fr)
AT (1) ATE324102T1 (fr)
AU (1) AU2002334935B2 (fr)
BR (1) BR0213155A (fr)
CA (1) CA2462338C (fr)
CO (1) CO5580739A2 (fr)
DE (1) DE60211004T2 (fr)
DK (1) DK1435916T3 (fr)
EA (1) EA006064B1 (fr)
ES (1) ES2261782T3 (fr)
HK (1) HK1069994A1 (fr)
HR (1) HRP20040334A2 (fr)
IL (1) IL160931A0 (fr)
MX (1) MXPA04003321A (fr)
NZ (1) NZ532759A (fr)
PL (1) PL368346A1 (fr)
RS (1) RS29104A (fr)
WO (1) WO2003030871A1 (fr)
ZA (1) ZA200402222B (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2265262A1 (es) * 2005-01-31 2007-02-01 Activery Biotech, S.L.(Titular Al 50%) Procedimiento para la obtencion de sistemas micro- y nanodispersos.
ES2292300A1 (es) * 2005-07-19 2008-03-01 Sociedad Española De Carburos Metalicos, S.A.(Titular Al 50%) Procedimiento para la obtencion de un material compuesto.

Families Citing this family (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2803538B1 (fr) * 1999-12-15 2002-06-07 Separex Sa Procede et dispositif de captage de fines particules par percolation dans un lit de granules
US7125453B2 (en) * 2002-01-31 2006-10-24 General Electric Company High temperature high pressure capsule for processing materials in supercritical fluids
US7063741B2 (en) * 2002-03-27 2006-06-20 General Electric Company High pressure high temperature growth of crystalline group III metal nitrides
US20040154985A1 (en) * 2003-02-07 2004-08-12 Ferro Corporation Method and apparatus for producing particles via supercritical fluid processing
US20060182808A1 (en) * 2003-04-29 2006-08-17 Akzo Nobel N.V. Antisolvent solidification process
WO2005034999A2 (fr) * 2003-10-10 2005-04-21 Bvm Holding Co. Composition pharmaceutique
WO2005053851A1 (fr) * 2003-11-26 2005-06-16 E.I. Dupont De Nemours And Company Systeme de broyage par corps broyants a pression elevee et procede de broyage de particules
US20050218076A1 (en) * 2004-03-31 2005-10-06 Eastman Kodak Company Process for the formation of particulate material
US7220456B2 (en) * 2004-03-31 2007-05-22 Eastman Kodak Company Process for the selective deposition of particulate material
WO2006042109A2 (fr) 2004-10-08 2006-04-20 Sdc Materials, Llc Appareil et procede d'echantillonnage et de collecte de poudres s'ecoulant dans un flux de gaz
US7704324B2 (en) * 2005-01-25 2010-04-27 General Electric Company Apparatus for processing materials in supercritical fluids and methods thereof
US20060275542A1 (en) * 2005-06-02 2006-12-07 Eastman Kodak Company Deposition of uniform layer of desired material
US20070013293A1 (en) * 2005-07-12 2007-01-18 Eastman Kodak Company OLED device having spacers
DE102005057685A1 (de) * 2005-12-01 2007-06-06 Boehringer Ingelheim Pharma Gmbh & Co. Kg Inhalator und Speicher für eine trockene Arzneimittelformulierung sowie diesbezügliche Verfahren und Verwendung
US7942970B2 (en) 2005-12-20 2011-05-17 Momentive Performance Materials Inc. Apparatus for making crystalline composition
FR2898516B1 (fr) * 2006-03-17 2008-05-30 Innov Ia Sa Procede de preparation d'une composition pulverulente et produit tel qu'obtenu
WO2008140786A1 (fr) 2007-05-11 2008-11-20 Sdc Materials, Inc. Procédé et appareil de production de nanoparticules ultra-petites et uniformes
US8481449B1 (en) 2007-10-15 2013-07-09 SDCmaterials, Inc. Method and system for forming plug and play oxide catalysts
CN102292072A (zh) * 2009-01-26 2011-12-21 特瓦制药工业有限公司 用微粒包衣载体的方法
FR2943539B1 (fr) * 2009-03-31 2011-07-22 Ethypharm Sa Composition pharmaceutique comprenant un macrolide immunosuppresseur de la famille des limus.
US9126191B2 (en) 2009-12-15 2015-09-08 SDCmaterials, Inc. Advanced catalysts for automotive applications
US8545652B1 (en) 2009-12-15 2013-10-01 SDCmaterials, Inc. Impact resistant material
US9119309B1 (en) 2009-12-15 2015-08-25 SDCmaterials, Inc. In situ oxide removal, dispersal and drying
US8470112B1 (en) 2009-12-15 2013-06-25 SDCmaterials, Inc. Workflow for novel composite materials
US9149797B2 (en) 2009-12-15 2015-10-06 SDCmaterials, Inc. Catalyst production method and system
US8652992B2 (en) 2009-12-15 2014-02-18 SDCmaterials, Inc. Pinning and affixing nano-active material
US8557727B2 (en) 2009-12-15 2013-10-15 SDCmaterials, Inc. Method of forming a catalyst with inhibited mobility of nano-active material
US8803025B2 (en) 2009-12-15 2014-08-12 SDCmaterials, Inc. Non-plugging D.C. plasma gun
KR101102834B1 (ko) 2010-02-24 2012-01-05 충남대학교산학협력단 신규한 리포좀 제조 방법 및 장치
US8669202B2 (en) 2011-02-23 2014-03-11 SDCmaterials, Inc. Wet chemical and plasma methods of forming stable PtPd catalysts
UA114600C2 (uk) * 2011-03-24 2017-07-10 Оцука Фармасьютікал Ко., Лтд. Фармацевтична композиція для лікування захворювання у порожнині рота, що містить ребаміпід
AU2012299065B2 (en) 2011-08-19 2015-06-04 SDCmaterials, Inc. Coated substrates for use in catalysis and catalytic converters and methods of coating substrates with washcoat compositions
US9511352B2 (en) 2012-11-21 2016-12-06 SDCmaterials, Inc. Three-way catalytic converter using nanoparticles
US9156025B2 (en) 2012-11-21 2015-10-13 SDCmaterials, Inc. Three-way catalytic converter using nanoparticles
RU2551578C2 (ru) * 2013-04-29 2015-05-27 Сергей Константинович Панюшин Сыпучий пищевой продукт
EP3024571B1 (fr) 2013-07-25 2020-05-27 Umicore AG & Co. KG Revêtements catalytiques et substrats revêtus pour convertisseurs catalytiques
EP3068517A4 (fr) 2013-10-22 2017-07-05 SDCMaterials, Inc. Compositions pour régénérer des pièges à nox
WO2015061477A1 (fr) 2013-10-22 2015-04-30 SDCmaterials, Inc. Conception de catalyseurs pour moteurs à combustion diesel de grande puissance
CN106470752A (zh) 2014-03-21 2017-03-01 Sdc材料公司 用于被动nox吸附(pna)系统的组合物
CN107913527B (zh) * 2016-10-11 2021-05-04 中石化石油工程技术服务有限公司 一种从油基钻屑中萃取非极性物质的方法及萃取装置

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5043280A (en) * 1987-12-28 1991-08-27 Schwarz Pharma Ag Method and apparatus for the manufacture of a product having a substance embedded in a carrier
WO1998017676A1 (fr) * 1996-10-24 1998-04-30 Glaxo Group Limited Nouvelle forme cristalline polymorphe de propionate de fluticasone, son procede de production et des compositions pharmaceutiques la renfermant
US5833891A (en) * 1996-10-09 1998-11-10 The University Of Kansas Methods for a particle precipitation and coating using near-critical and supercritical antisolvents
WO1998052544A1 (fr) * 1997-05-23 1998-11-26 Astra Aktiebolag Composition comprenant des particules de budesonide cristallines finement divisees

Family Cites Families (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4582731A (en) 1983-09-01 1986-04-15 Battelle Memorial Institute Supercritical fluid molecular spray film deposition and powder formation
US4734451A (en) 1983-09-01 1988-03-29 Battelle Memorial Institute Supercritical fluid molecular spray thin films and fine powders
DE3536622A1 (de) 1985-10-15 1987-04-16 Krupp Gmbh Verfahren und vorrichtung zur gewinnung fester stoffe aus fluessigen stoffgemischen
US5707634A (en) 1988-10-05 1998-01-13 Pharmacia & Upjohn Company Finely divided solid crystalline powders via precipitation into an anti-solvent
EP0388915B1 (fr) 1989-03-22 1993-10-06 Union Carbide Chemicals And Plastics Company, Inc. Compositions précurseurs de revêtement
US5360478A (en) 1989-10-16 1994-11-01 Phasex Corporation Gas anti-solvent recrystallization process
US4970093A (en) 1990-04-12 1990-11-13 University Of Colorado Foundation Chemical deposition methods using supercritical fluid solutions
US6063910A (en) 1991-11-14 2000-05-16 The Trustees Of Princeton University Preparation of protein microparticles by supercritical fluid precipitation
US5301664A (en) 1992-03-06 1994-04-12 Sievers Robert E Methods and apparatus for drug delivery using supercritical solutions
US5639441A (en) 1992-03-06 1997-06-17 Board Of Regents Of University Of Colorado Methods for fine particle formation
US5389263A (en) 1992-05-20 1995-02-14 Phasex Corporation Gas anti-solvent recrystallization and application for the separation and subsequent processing of RDX and HMX
AU5171293A (en) 1992-10-14 1994-05-09 Regents Of The University Of Colorado, The Ion-pairing of drugs for improved efficacy and delivery
US5290604A (en) * 1992-12-18 1994-03-01 Union Carbide Chemicals & Plastics Technology Corporation Methods and apparatus for spraying solvent-borne compositions with reduced solvent emission using compressed fluids and separating solvent
GB9313650D0 (en) 1993-07-01 1993-08-18 Glaxo Group Ltd Method and apparatus for the formation of particles
GB9313642D0 (en) 1993-07-01 1993-08-18 Glaxo Group Ltd Method and apparatus for the formation of particles
GB9413202D0 (en) 1994-06-30 1994-08-24 Univ Bradford Method and apparatus for the formation of particles
EP0706821A1 (fr) 1994-10-06 1996-04-17 Centre De Microencapsulation Procédé pour l'enrobage de particules
US5803966A (en) 1995-11-01 1998-09-08 Alcon Laboratories, Inc. Process for sizing prednisolone acetate using a supercritical fluid anti-solvent
US5874029A (en) 1996-10-09 1999-02-23 The University Of Kansas Methods for particle micronization and nanonization by recrystallization from organic solutions sprayed into a compressed antisolvent
SE9804001D0 (sv) 1998-11-23 1998-11-23 Astra Ab New process
US6248363B1 (en) * 1999-11-23 2001-06-19 Lipocine, Inc. Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
ES2240222T3 (es) * 1999-12-20 2005-10-16 Nicholas J. Kerkhof Procedimiento para producir particulas nanometricas mediante secado por pulverizacion en lecho fluidizado.
BR0108912A (pt) 2000-03-03 2002-12-24 Boehringer Ingelheim Pharma Processamento de material por expansão-contração de solvente repetido
US8137699B2 (en) * 2002-03-29 2012-03-20 Trustees Of Princeton University Process and apparatuses for preparing nanoparticle compositions with amphiphilic copolymers and their use

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5043280A (en) * 1987-12-28 1991-08-27 Schwarz Pharma Ag Method and apparatus for the manufacture of a product having a substance embedded in a carrier
US5833891A (en) * 1996-10-09 1998-11-10 The University Of Kansas Methods for a particle precipitation and coating using near-critical and supercritical antisolvents
WO1998017676A1 (fr) * 1996-10-24 1998-04-30 Glaxo Group Limited Nouvelle forme cristalline polymorphe de propionate de fluticasone, son procede de production et des compositions pharmaceutiques la renfermant
WO1998052544A1 (fr) * 1997-05-23 1998-11-26 Astra Aktiebolag Composition comprenant des particules de budesonide cristallines finement divisees

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2265262A1 (es) * 2005-01-31 2007-02-01 Activery Biotech, S.L.(Titular Al 50%) Procedimiento para la obtencion de sistemas micro- y nanodispersos.
US7754777B2 (en) 2005-01-31 2010-07-13 Sociedad Espanola De Carburos Metalicos, S.A. Method for obtaining micro- and nano-disperse systems
ES2292300A1 (es) * 2005-07-19 2008-03-01 Sociedad Española De Carburos Metalicos, S.A.(Titular Al 50%) Procedimiento para la obtencion de un material compuesto.

Also Published As

Publication number Publication date
MXPA04003321A (es) 2004-07-23
KR20050035146A (ko) 2005-04-15
CA2462338A1 (fr) 2003-04-17
DE60211004T2 (de) 2006-08-31
EP1435916A1 (fr) 2004-07-14
US20030066800A1 (en) 2003-04-10
AU2002334935B2 (en) 2008-04-03
HK1069994A1 (en) 2005-06-10
DE60211004D1 (de) 2006-06-01
JP2005511521A (ja) 2005-04-28
PL368346A1 (en) 2005-03-21
JP4778997B2 (ja) 2011-09-21
NZ532759A (en) 2005-10-28
ES2261782T3 (es) 2006-11-16
IL160931A0 (en) 2004-08-31
ATE324102T1 (de) 2006-05-15
CA2462338C (fr) 2011-04-19
CN1568179A (zh) 2005-01-19
CO5580739A2 (es) 2005-11-30
ZA200402222B (en) 2006-05-31
US6858166B2 (en) 2005-02-22
HRP20040334A2 (en) 2004-08-31
RS29104A (en) 2006-12-15
EP1435916B1 (fr) 2006-04-26
DK1435916T3 (da) 2006-08-21
CN1273113C (zh) 2006-09-06
EA200400483A1 (ru) 2004-10-28
BR0213155A (pt) 2004-09-14
EA006064B1 (ru) 2005-08-25
JP2009051842A (ja) 2009-03-12

Similar Documents

Publication Publication Date Title
CA2462338C (fr) Traitement de poudre avec des fluides gazeux sous pression
AU2002334935A1 (en) Powder processing with pressurized gaseous fluids
Bleich et al. Production of drug loaded microparticles by the use of supercritical gases with the aerosol solvent extraction system (ASES) process
Freitas et al. Ultrasonic atomisation into reduced pressure atmosphere—envisaging aseptic spray-drying for microencapsulation
JP3806107B2 (ja) 粒子を形成するための方法及び装置
York Strategies for particle design using supercritical fluid technologies
Caliceti et al. Effective protein release from PEG/PLA nano-particles produced by compressed gas anti-solvent precipitation techniques
Jain et al. Spray drying in pharmaceutical industry: A review
JP5358948B2 (ja) 粉末の被覆方法
Matos et al. Dense CO2 technology: Overview of recent applications for drug processing/formulation/delivery
Tan et al. Particle formation using supercritical fluids: pharmaceutical applications
Wang et al. Extraction and precipitation particle coating using supercritical CO2
Sin Cheow et al. Towards sustainability: new approaches to nano-drug preparation
Charbit et al. Methods of particle production
Valle et al. Supercritical fluid technique for particle engineering: drug delivery applications
Foster et al. Particle engineering by dense gas technologies applied to pharmaceuticals
Wahl Supercritical fluid technology
Galán et al. The Encapsulation Art: Scale‐up and Applications
Wakure et al. Supercritical fluid technology: Nascent contrivance for pharmaceutical product development
WO2007009986A2 (fr) Procede pour obtenir un composite
SA JOEL RICHARD Ethypharm SA, Saint-Cloud, France
Kluge et al. PRODUCTION OF POLYMER MICROPARTICLES FOR PHARMACEUTICAL APPLICATIONS BY SUPERCRITICAL FLUID EXTRACTION OF EMULSIONS
HU227115B1 (en) Pellets containing pyridazinone derivative

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 1200400289

Country of ref document: VN

Ref document number: P-291/04

Country of ref document: YU

AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BY BZ CA CH CN CO CR CU CZ DE DM DZ EC EE ES FI GB GD GE GH HR HU ID IL IN IS JP KE KG KP KR LC LK LR LS LT LU LV MA MD MG MN MW MX MZ NO NZ OM PH PL PT RU SD SE SG SI SK SL TJ TM TN TR TZ UA UG UZ VC VN YU ZA ZM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ UG ZM ZW AM AZ BY KG KZ RU TJ TM AT BE BG CH CY CZ DK EE ES FI FR GB GR IE IT LU MC PT SE SK TR BF BJ CF CG CI GA GN GQ GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 160931

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 2002800989

Country of ref document: EP

Ref document number: 2004/02222

Country of ref document: ZA

Ref document number: 200402222

Country of ref document: ZA

WWE Wipo information: entry into national phase

Ref document number: 2462338

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 00813/DELNP/2004

Country of ref document: IN

Ref document number: 813/DELNP/2004

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: PA/a/2004/003321

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: P20040334A

Country of ref document: HR

WWE Wipo information: entry into national phase

Ref document number: 2003533904

Country of ref document: JP

Ref document number: 1020047005297

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 20028201183

Country of ref document: CN

WWE Wipo information: entry into national phase

Ref document number: 2002334935

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 04034727

Country of ref document: CO

WWE Wipo information: entry into national phase

Ref document number: 200400483

Country of ref document: EA

WWE Wipo information: entry into national phase

Ref document number: 1-2004-500486

Country of ref document: PH

WWE Wipo information: entry into national phase

Ref document number: 532759

Country of ref document: NZ

WWP Wipo information: published in national office

Ref document number: 2002800989

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 532759

Country of ref document: NZ

WWG Wipo information: grant in national office

Ref document number: 532759

Country of ref document: NZ

WWG Wipo information: grant in national office

Ref document number: 2002800989

Country of ref document: EP